The tocopherol is generally well known as vitamin E. The tocopherol is much contained in vegetable oils such as peanut oil and soybean oil.
The vitamin E, i.e., tocopherol has been studied for the elucidation of the antisterile effect thereof. What has attracted the greatest interest during the study is the antioxidant effect of tocopherol. Further, extensive biologic effects have recently been recognized of tocopherols inclusive of tocopherol and salts thereof.
These effects of the tocopherols have been noted and, now, the tocopherols are used in a wide range of application fields such as not only pharmaceutical preparations, cosmetic ingredients and livestock feed additives but also food, health food and plastic additives.
However, the tocopherols have drawbacks in that they are insoluble in water although being soluble in fats and oils and organic solvents such as acetone and ethanol and are viscous and oily, so that the handling thereof is restricted and that they are easily oxidized by the action of light, heat, alkali, etc. in the air.
Accordingly, in recent years, extensive studies are made on, for example, converting the tocopherol to derivatives in order to increase the hydrophilicity thereof. Examples of such attempts to increase hydrophilicity of the tocopherol include the synthesis of a phosphoric diester of tocopherylglycerol and a salt thereof (see Japanese Patent Laid-open Publication No. 6(1994)-87875), the synthesis of a tocopherol glycoside (see, for example, Japanese Patent Laid-open Publication No. 60(1985)-56994) and the synthesis of an ethylene glycol derivative of tocopheryl phosphate (see Yakugaku Zasshi, 75, 1322 (1955) and Chem. Pharm. Bull., 19, 687 (1971)). Further, examples of the above attempts include the synthesis of a phosphoric diester of L-ascorbic acid/dltocopherol (see Japanese Patent Laid-open Publication Nos. 59(1984)-219295, 62(1987)-205091 and 02(1990)-111722).
However, all the tocopherol derivatives disclosed in the above literature must be synthesized through multiple stages of reactions, so that the problems are encountered that the production involves difficulty and the cost is high.
Moreover, an aqueous emulsion composition containing a tocopherol in high concentration has been proposed in Japanese Patent Publication No. 7(1995)-037381, which specifically contains an alkali metal salt of hemisuccinic ester of tocopheryl phosphate but contains none of a dissolution auxiliary and an emulsifier. Further, tocopheryl nicotinates have been proposed (see, for example, Japanese Patent Publication No. 55(1980)-049074).
However, the compounds described in these literature, like those described in the above literature, must be synthesized through multiple stages of reactions, so that the problems are encountered that the production involves difficulty and the cost is high. Further, they are scarcely soluble in water, so that the problem is encountered that the addition thereof to a wide variety of cosmetic preparations is difficult.
It has been reported that a sodium salt of tocopheryl phosphate is a hydrophilic tocopherol derivative whose synthesis is relatively easy (see Yakugaku Zasshi, 75, 1322 (1955), Japanese Patent Publication Nos. 37(1962)-1737 and 03(1991)-32558 and Khim.-Fram. Zh., 17(7), 840 (1983)).
However, Nakagawa et al. have described in the pharmaceutical journal (Yakugaku Zasshi, 75(11), 1322 (1955)) that an aqueous solution of tocopheryl phosphate obtained by the reaction of tocopherol with an oxyphosphorus trichloride is emulsified, when brought into about neutrality, or form precipitates, which are not readily soluble in water.
E. E. Zhukova et al. have described in the journal (Khim.-Fram. Zh., 17(7), 840 (1983)) that a tocopheryl phosphate can be obtained by reacting an oxyphosphorus trichloride substituted with a protective group with a tocopherol and removing the protective group but the yield is low and that only a disodium salt is soluble in water, that is, the tocopheryl phosphate is soluble only at a basicity of at least 10 in pH.
The inventors have made extensive studies with a view toward solving the above problems. As a result, it has been found that the alkali metal of tocopheryl phosphate is emulsified or precipitated at about neutrality for the following reason.
That is, it has been found that when an oxyphosphorus trihalide is reacted with a tocopherol in the presence of a deacidation agent such as pyridine and the phosphorus-halogen bond of the reaction product is hydrolyzed, not only is the tocopheryl phosphate obtained but also an impurity of P,P'-bistocopheryl diphosphate is formed as a by-product. It has further been found that this P,P'-bistocopheryl diphosphate has a low solubility in a neutral aqueous solution, so that a solid is precipitated from an aqueous solution in which a certain level of the P,P'-bistocopheryl diphosphate is contained, thereby causing clouding and precipitation.
The inventors have made further extensive studies on the basis of the above finding. As a result, it has been found that an aqueous solution of tocopheryl phosphates which is clear at neutrality can be obtained either by performing a specified treatment of the above mixture of tocopheryl phosphate and P,P'-bistocopheryl diphosphate under specified conditions to thereby effect a selective decomposition of the P,P'-bistocopheryl diphosphate or by reacting a tocopherol with an oxyphosphorus trihalide and, thereafter, treating the reaction mixture by a specified method so that the tocopheryl phosphate is produced under conditions such that none of P,P'-bistocopheryl diphosphate is formed or the formation thereof is minimized. The present invention has been completed on the basis of this finding.
In connection with the cosmetic, the conventional preparations containing tocopheryl phosphates and process for producing the same have involved the following problems.
That is, the addition of the tocopheryl phosphate and/or salt thereof which has been produced by the conventional synthetic method to a cosmetic has involved the problem that the tocopheryl phosphate or salt thereof is soluble to an appreciable degree in an alkali aqueous solvent but scarcely soluble in a nearly neutral aqueous solvent of 5 to 9 in pH which is commonly employed in cosmetic use, so that the addition thereof to a wide variety of cosmetic preparations is difficult. In particular, the addition of the tocopheryl phosphate which has been produced by the conventional synthetic method to a cosmetic having a high water content such as toilet water which is a mainstream of the recent cosmetic has involved the problem that troubles such as changing of viscosity, breaking of emulsification and precipitation of insoluble matter in the preparation with the passage of time occur to thereby gravely deteriorate the quality of the cosmetic.
The method in which, for example, a nonionic surfactant is added to the tocopheryl phosphate to thereby emulsify and disperse the same as mentioned hereinbefore (see Japanese Patent Publication No. 03(1991)-32558) is known as means for solving the above problems. However, this method has drawbacks in that an additional emulsification step must be provided to thereby complicate the process and that an emulsion type cosmetic results to thereby cause heavy feeling and disenable production of a transparent toilet water which is a mainstream of the recent cosmetic. Further, the problem has been encountered that a cosmetic preparation whose time stability is satisfactory from the viewpoint of a stability test over a period as long as three years at room temperature, a stability test at about neutrality and an accelerated test at 40.degree. C. which cosmetics should pass cannot be obtained.
In contrast, the above process for producing highly purified tocopheryl phosphates and the highly purified tocopheryl phosphates produced by this process, which have been completed by the inventors, are advantageous over the prior art in that the amount of impurities is very small and the tocopheryl phosphates have high solubility, do not form precipitates at neutrality irrespective of the passage of time and can suitably be added to cosmetics.
In the prior art process, as mentioned above, the tocopheryl phosphate is produced by reacting an oxyphosphorus trihalide with a tocopherol in the presence of pyridine and hydrolyzing the phosphorus-halogen bond of the reaction product in alkali condition. That the formation of not only the tocopheryl phosphate but also an impurity of P,P'-bistocopheryl diphosphate is inevitable in this prior art process has been confirmed by an analytical method for impurities made by the present inventors.
As a result of the inventors' studies, it has been found that the P,P'-bistocopheryl diphosphate has poor solubility in water, especially low solubility in water at neutrality of 5 to 9 in pH, so that the addition thereof to cosmetics would cause the P,P'-bistocopheryl diphosphate to crystallize in the preparation with the passage of time to thereby form precipitates.
Therefore, it is required to control the content of P,P'-bistocopheryl diphoshate and, accordingly, to establish the method of measuring the quantity thereof and develop means for selectively decomposing and removing the P,P'-bistocopheryl diphoshate, for obtaining the cosmetic preparation of tocopheryl phosphate which is stable at neutrality.
It is common to conduct an analysis of tocopheryl phosphates in most cases by ultraviolet/visible radiation spectroscopy or .sup.31 P-NMR (see, for example, Bioact. Mol., 3, 235 (1987)). With the use of such an analytical method, however, it has been difficult to determine the ratio of content of tocopheryl phosphate to P,P'-bistocopheryl diphoshate when the P,P'-bistocopheryl diphoshate is contained in a sample only in an amount of as small as about a few percents. Further, the content of a compound containing no phosphorus atoms such as tocopherol as a starting material cannot be measured by such an analytical method, and there has been the problem that the preparation of an analytical sample and the measurement thereof consume a relatively large amount of workload and time. Thus, there is no method for obtaining a highly purified tocopheryl phosphate on the basis of an accurate measurement of the content of such impurities. The use of the tocopheryl phosphate obtained in the prior art invites the mixing of impurities into the cosmetic to thereby not only threaten the safety of the cosmetic but also cause the danger of deterioration of the quality of the cosmetic preparation, especially, occurrence of sediments with the passage of time. Therefore, the use of tocopheryl phosphates as cosmetic ingredients has been under extensive restraints.
The inventors have solved these problems and have also completed an analytical method which enables readily detecting tocopheryl phosphates and measuring the content thereof with high precision.